Project Summary/ Abstract A network of neural structures crucial for the cognitive and behavioral processes of drug addiction, including nicotine, includes the orbitofrontal cortex, anterior cingulate, insular cortices, the amygdala, and the striatum. However, no work has addressed how damage to different components of this neural network in humans may impact the maintenance of addiction to drugs. Under the tenure of an R21 awarded through CEBRA (Cutting- Edge Basic Research Awards), we began addressing this important issue in patients addicted to cigarette smoking and who had suffered a stroke that included any of these areas. It was found that although lesions of the ventromedial prefrontal cortex (VMPFC) were associated with a marked impairment of cue-induced urge in the laboratory, they were not associated with an increased likelihood of quitting smoking. In fact, lesions of the insular cortex were associated with an ability to quit smoking easily, immediately, without relapses and without a lasting urge to smoke. Although preliminary, these results suggest that, while VMPFC lesions may disrupt cue-induced urges, they do not disrupt smoking addiction. However, the insula, which also plays a key role in urges, seems most critical for maintaining smoking addiction and driving smoking behavior. The results also suggest that the insula functions in psychological processes that may contribute to the difficulty of quitting smoking. Encouraged by these intriguing, but preliminary, results, our primary aims are to (1) expand and confirm these findings in a larger sample, using more precise anatomical analyses to characterize the size and placement of lesions; (2) examine whether there are gender differences in terms of the ease to quit smoking after a lesion; and (3) conduct prospective studies on smokers who suffer strokes and monitor their smoking behavior for several years after the lesion onset. The proposed research is a beginning of a novel approach with potential for developing more effective therapies for breaking the vicious cycle of addiction. Specifically, one therapeutic approach called up by the proposed research would be to directly modulate the function of the insula. Project Narrative A prune-sized region deep in the brain called the insula is intimately involved in smoking addiction, and damage to this structure can completely erase the body's urge to smoke. Obviously brain damage is not a treatment option for nicotine addiction, but if confirmed, these results may offer leads for therapies to help smokers kick the habit, or for monitoring smokers' progress while using existing therapies.